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A study of new therapeutic candidates for Alzheimer's disease utilizing microglia activation by

利用小胶质细胞激活治疗阿尔茨海默病的新候选药物的研究

基本信息

批准号：
17590138
负责人：
OKA Jun-Ichiro
金额：
$ 2.24万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590138/
关键词：
GLP-1 microglia astrocyte IL-1β GLT-1 inflammation excitotoxicity neurodegenerative disease アストログリア cAMP CREB 認知症

项目摘要

In the early stage of Alzheimer's disease, neuroinflammation is considered to be important, and cytokines released from glia play a role in progression of the phenomena. Since lipopolysaccharide (LPS) could experimentally induce similar inflammatory changes in the brain, we examined the effects of glucagon-like peptide-1 (GLP-1) on LPS-induced cytokine expression in cultured astrocytes derived from the E18 rat's cortex. RT-PCR analysis showed that GLP-1 suppressed LPS-induced IL-β,IL-6 and iNOS expressions. Furthermore, ELISA demonstrated that peptide levels of IL-1β in the culture medium decreased in response to GLP-1 through the cAMP system and CREB phosphorylation. Furthermore, we investigated the effects of GLP-1 on the glial glutamate transporter, GLT-1, mRNA expression, since a decrease in glutamate transporters in Alzheimer's disease, and an inhibition of glutamate uptake into glia by (3-amyloid protein were reported, which phenomena may result in an increase in excitotoxicity by glutamate. GLP-1 treatment increased the GLT-1 mRNA expression in cultured astrocytes. We suggest that GLP-1 may protect neurons from excitotoxicity through an increase in glial glutamate transporters in the pathological conditions of the central nervous system. These results suggest that GLP-1 has neuroprotective effects through the inhibition of excitotoxicity as well as suppression of pro-inflammatory cytokines production after microglia activation.

在阿尔茨海默病的早期阶段，神经炎症被认为是重要的，并且从胶质细胞释放的细胞因子在该现象的进展中起作用。由于脂多糖（LPS）可以在实验中诱导类似的炎症变化，在大脑中，我们研究了胰高血糖素样肽-1（GLP-1）对LPS诱导的细胞因子表达的影响，培养的星形胶质细胞来自E18大鼠的皮质。RT-PCR分析显示GLP-1抑制LPS诱导的IL-β、IL-6和iNOS的表达。此外，ELISA表明，培养液中IL-1β的肽水平响应于GLP-1通过cAMP系统和CREB磷酸化而降低。此外，我们研究了GLP-1对神经胶质谷氨酸转运蛋白GLT-1 mRNA表达的影响，因为据报道，阿尔茨海默病中谷氨酸转运蛋白减少，β-淀粉样蛋白抑制谷氨酸摄取进入神经胶质，这一现象可能导致谷氨酸兴奋毒性增加。GLP-1处理增加了培养的星形胶质细胞中GLT-1 mRNA的表达。我们认为，GLP-1可能通过增加神经胶质谷氨酸转运蛋白在中枢神经系统的病理条件下保护神经元免受兴奋性毒性。这些结果表明，GLP-1通过抑制兴奋性毒性以及抑制小胶质细胞活化后促炎细胞因子的产生而具有神经保护作用。